DESCRIPTION (adapted from the application) Type 2 diabetes is characterized by insulin resistance and beta-cell failure resulting in uncontrolled hyperglycemia. The basis of the beta-cell defect is presently unclear. A growing body of evidence indicates insulin-signaling proteins are present in the islets and contribute to the maintenance of glucose homeostasis. Thus, normal beta-cells show glucose-stimulated phosphorylation of the insulin receptor (IR) and insulin receptor substrate-1 (IRS-1). Secondly, mice with a targeted disruption of the IR show loss of insulin secretory response to glucose and progressive glucose intolerance. Third, primary islets and beta-cell lines derived from IRS-1 knockout mice show reduced insulin content and blunted secretory responses to multiple stimuli, and IRS-2 knockout mice manifest a defect in beta-cell development. These data indicate the presence of an insulin-signaling pathway in the islets/beta-cells potentially linked to glucose signaling that plays an important role in islet function. The goals of this proposal are to understand the mechanisms by which the insulin-signaling proteins modulate beta-cell function and to delineate the cross-talk between the insulin- and glucose-signaling pathways. Our studies will be directed at the following specific aims: 1) to identify the cellular mechanisms by which proteins in the insulin-signaling pathway modulate insulin secretion and synthesis in response to different stimuli, 2) to determine the alterations in glucose metabolism in islets/beta-cells isolated from mice lacking the IR and the IRS proteins and to study the effects of re-expression of the proteins in the knockout cell lines, and 3) to evaluate the expression of insulin signaling proteins and glucose metabolism in islets isolated from rodent models of diabetes. My earlier training in islet physiology and metabolism and the experience I am currently gaining as a research fellow at the Joslin Diabetes Center have provided me with a unique perspective to explore the significance of the insulin signaling pathway in islet/beta-cell function. The mentoring support of Prof. Kahn and the academic environment of the Joslin Diabetes Center and Harvard Medical School provides me with an excellent opportunity to continue my investigation in type 2 diabetes and further develop my skills to attain my goals as an independent investigator.